1. Field of the Invention
This invention pertains in general to the field of treatment of neuropathy, such as diabetic peripheral neuropathy, vaso-constrictive disorders, macro-angiopathy and slow healing wounds as consequence of diabetic neuropathy and impaired blood circulation due to diabetic disease or obstructed blood flow caused by other disease. More particularly the invention relates to a device for treatment of at least some of said disorders, and a process for manufacturing of said device, involving the use of nitric oxide (NO).
2. Description of the Related Art
Diabetes is a disorder that affects millions of people around the world. This disease results in increased risk for neuropathy and macro-angiopathy. Reasons for diabetic neuropathy may be varying levels of insulin or blood sugar respectively, and high blood sugar. Diabetic neuropathy, or nerve damage, resulting from chronically high blood sugars, can be one of the most frustrating and debilitating complications of diabetes, because of the pain, discomfort and disability it can cause, and because available treatments are not uniformly successful.
Diabetic neuropathy may be divided into the three main types of neuropathy; sensory neuropathy, autonomic neuropathy, and motor neuropathy. Sensory neuropathy leads to pain, numbness, tingling in the extremities, and even the inability to feel heat, cold, pain or any other sensation in the affected areas. Autonomic neuropathy leads to impotence (in men), bladder neuropathy, diabetic diarrhea, or swollen stomach. Motor neuropathy leads to muscle weakness.
As a direct and indirect consequence of diabetic neuropathy the person suffering from this disorder may develop ulcers, so-called diabetic ulcers. These diabetic ulcers may develop as a result of small traumas on the body. Since the diabetic person, suffering from diabetic neuropathy, has a reduced, and some times even non-existent, ability to feel, these ulcers may develop very rapidly. Other factors that severely affect this matter are the reduced ability to heal and the reduced circulation in the affected area, which accompanies diabetic neuropathy. The reduced circulation in the affected area is a consequence of macro-angiopathy. Macro-angiopathy is a condition in which the blood vessels are enlarged and the arteries are hardened. These ulcers often result in amputation of the affected extremity. Macro-angiopathy is closely related to Peripheral Artery Obstructive Disease, and will therefore here on after be treated as the same.
Other malfunctions arising from diabetic neuropathy are vaso-constrictive disorders, such as Raynouds, or Reyes syndrome.
Up to this point in time, there are no good cures or treatment of neuropathy. Some medications, such as acetaminophen, aspirin, ibuprofen, amitriptyline, desipramine, and capsaicin, are on the market to liberate the diabetic person from pain, but these medicaments do not deal with the malfunction itself, only with the symptoms, and sometimes develop resistance against the active pharmaceutical substance in the medication. The person suffering from said disorders is instructed to apply these medicaments in form of creams and peroral compositions regularly during the day, rather than waiting for the pain to become severe. This is an all day process, which is very frustrating for the person suffering from said disorders. It is believed, in some circumstances, that these creams and compositions block pain signals, although they do not work for everyone. Occasionally, these creams and compositions may even worsen the pain or cause other adverse effects, such as eye or skin irritation. In the late 1980s and early 1990s aldose reductase inhibitors were introduced. Unfortunately, to date none of these drugs has proven to be sufficiently effective and adverse side effects have been a concern. Instead, the best advice the person suffering from said disorder can get, is to control and regulate his/her way of living, such as keeping blood sugar levels as close to normal as possible, exercise regularly, and take care of their health and weight.
It is known that nitric oxide (NO) provides an alternative to conventional therapies, such as antibiotics. Nitric oxide is a highly reactive molecule that is involved in many cell functions. In fact, nitric oxide plays a crucial role in the immune system and is utilized as an effector molecule by macrophages to protect itself against a number of pathogens, such as fungi, viruses, bacteria etc., and general microbial invasion. This improvement of healing is partly caused by NO inhibiting the activation or aggregation of blood platelets, and also by NO causing a reduction of inflammatory processes at the site of an implant.
NO is also known to have an anti-pathogenic, especially an anti-viral, effect, and furthermore NO has an anti-cancerous effect, as it is cytotoxic and cytostatic in therapeutic concentrations, i.e. it has among other effects tumoricidal and bacteriocidal effects. NO has for instance cytotoxic effects on human hematological malignant cells from patients with leukemia or lymphoma, whereby NO may be used as a chemotherapeutic agent for treating such hematological disorders, even when the cells have become resistant to conventional anti-cancer drugs.
However, due to the short half-life of NO, it has hitherto been very hard to treat viral, bacteria, virus, fungi or yeast infections with NO. This is because NO is actually toxic in high concentrations and has negative effects when applied in too large amounts to the body. NO is actually also a vasodilator, and too large amounts of NO introduced into the body will cause a complete collapse of the circulatory system. On the other hand, NO has a very short half-life of fractions of a second up to a few seconds, once it is released. Hence, administration limitations due to short half-life and toxicity of NO have been limiting factors in the use of NO in the field of anti-pathogenic and anti-cancerous treatment so far.
In recent years research has been directed to polymers with the capability of releasing nitrogen oxide when getting in contact with water. Such polymers are for example polyalkyleneimines, such as L-PEI (Linear PolyEthyleneImine) and B-PEI (Branched PolyEthyleneImine), which polymers have the advantage of being biocompatible.
U.S. Pat. No. 5,519,020 describes water insoluble polymeric NONOate complexes, such as PEI-C and S-nitroso-compounds, which are capable of accelerating wound repair through the controlled therapeutic release of NO. Clinical applications of the device according to U.S. Pat. No. 5,519,020 include treatment of burns, burn donor sites, chronic venous ulcers, decubitus ulcers, leprous ulcers, epidermolysis bullosa, scleroderma, psoriasis, and non infected partial thickness wounds. However, the elution of nitric oxide from the polymer according to U.S. Pat. No. 5,519,020 is not regulated in any way. Furthermore, U.S. Pat. No. 5,519,020 is totally silent about the treatment of neuropathy.
Bohl Masters et al. (Wound Repair Regeneration, 10((5):286-294, 2002 XP002335426 US) describes in vitro and in vivo responses to a novel hydrogel, manufactured by ultraviolet light-initiated polymerization from poly(vinyl alcohol) with a NO donor covalently coupled to the polymer backbone, that produces therapeutic levels of NO. (However, the elution is not regulated in any way. Furthermore, this document is totally silent about the treatment of neuropathy.
U.S. Pat. No. 6,737,447 discloses a coating for medical devices, which coating provides NO delivery by using nanofibers of L-PEI. However, the elution of nitric oxide from the polymer according to U.S. Pat. No. 6,737,447 is not regulated in any way. Furthermore, U.S. Pat. No. 6,737,447 is totally silent about the treatment of neuropathy.
EP 1 300 424 discloses extremely hydrophobic NO releasing polymers. These polymers are extensively cross-linked polyamine-derivatized divinylbenzene diazeniumdiolates. However, the elution of nitric oxide from the polymer according to EP 1 300 424 is not regulated in any way. Furthermore, EP 1 300 424 is totally silent about the treatment of neuropathy.
US 2004/0171589 discloses local, differential delivery of nitric oxide within the body. US 2004/0171589 mentions that the device according to US 2004/0171589 may be used for placement on skin wounds or openings, page 2, left column, lines 5 to 6. Furthermore, US 2004/0171589 discloses polyethyleneimine microspheres, with an attached diazeniumdiolate moiety, for long in-situ half-life applications, page 6, right column, lines 1 to 5. However, the elution of nitric oxide from the polymer according to US 2004/0171589 is not regulated in any way. Furthermore, US 2004/0171589 is totally silent about the treatment of neuropathy.
Other example for NO eluting polymers are given in U.S. Pat. No. 5,770,645, wherein polymers derivatized with at least one —NOX group per 1200 atomic mass unit of the polymer are disclosed, X being one or two. One example is an S-nitrosylated polymer and is prepared by reacting a polythiolated polymer with a nitrosylating agent under conditions suitable for nitrosylating free thiol groups.
Akron University has developed NO-eluting L-PEI molecule that can be nano-spun onto the surface of permanently implanted medical devices such as implanted grafts, showing significant improvement of the healing process and reduced inflammation when implanting such devices. According to U.S. Pat. No. 6,737,447, a coating for medical devices provides nitric oxide delivery using nanofibers of linear poly(ethylenimine)-diazeniumdiolate. Linear poly(ethylenimine)diazeniumdiolate releases nitric oxide (NO) in a controlled manner to tissues and organs to aid the healing process and to prevent injury to tissues at risk of injury.
However, the meaning of “controlled” in the context of U.S. Pat. No. 6,737,447 is only directed to the fact that nitric oxide is eluted from the coating during a period of time. Therefore, the interpretation of “controlled” in respect of U.S. Pat. No. 6,737,447 is different from the meaning of “regulating” in the present invention. “Regulate”, according to the present invention is intended to be interpreted as the possibility to vary the elution of nitric oxide to thereby achieve different elution profiles.
Electrospun nanofibers of linear poly(ethylenimine)diazeniumdiolate deliver therapeutic levels of NO to the tissues surrounding a medical device while minimizing the alteration of the properties of the device. A nanofiber coating, because of the small size and large surface area per unit mass of the nanofibers, provides a much larger surface area per unit mass while minimizing changes in other properties of the device.
However, the disclosure is both silent concerning an improvement of present technology in respect of treatment of neuropathy, such as diabetic neuropathy, diabetic ulcers, vaso-constrictive disorders, and enlarged and hardened blood vessels, and the anti pathogenic potential of nitric oxide.
Hence, an improved, or more advantageous, device for therapeutic treatment and/or prevention of neuropathy, such as diabetic neuropathy, diabetic ulcers, and macro-angiopathy is needed. It is desired that said device does increase circulation in the affected area while affecting nerves positively, has a vaso-dilating effect, reduces pain and heals wounds, which device is easy to use, and cost effective, and which device does not develop resistance against the active pharmaceutical substance, and which does not cause local skin or eye irritation, pain etc, and in particular a device allowing for target prevention and treatment of neuropathy, such as diabetic neuropathy, diabetic ulcers, and enlarged and hardened blood vessels, would be advantageous.